The Bethesda Handbook of Clinical Oncology

Gastrointestinal Stromal Tumors (GIST) 8

Dale R. Shepard and Alok A. Khorana

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract. Most GIST tumors have a mutation in the proto-oncogene KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes. Ideally, these tumors are resected, which is curative for many patients. The development of targeted therapies that inhibit KIT and PDGFRA has revolutionized recurrence after surgery and the treatment of metastatic disease.

EPIDEMIOLOGY

The incidence of GIST in the United States is approximately 7 to 20 per 1,000,000 people leading to 4000 to 6000 new cases annually. The majority of cases are sporadic with patients having no family history of GIST. In a SEER registry, the median age at diagnosis was 63 years of age. There are no established risk factors for the development of most GIST, although some conditions, including neurofibromatosis-1 (NF-1), are associated with the development of GIST.

PATHOLOGY

GIST originate from interstitial cells of Cajal. It is important to differentiate GIST from other subepithelial tumors of the GI tract, including leiomyosarcoma, leiomyoma, and desmoid tumors. GIST can be identified by the presence of KIT overexpression, present in 95% of GIST, or KIT mutations that are present in 80% of GISTs. DOG-1 is another sensitive and specific marker for diagnosis of GIST. Among KIT mutations, 70% are found on exon 11 and 10% on exon 9; exons 13 and 17 are rarely involved. Alterations in KIT, a transmembrane receptor tyrosine kinase, lead to activation of the transmembrane receptor and abnormal cell signaling. These KIT alterations can be detected by immunohistochemistry with anti-CD117 antibodies. GIST tumors may also have mutations in PDGFRA. PDGFRA mutations are homologous to those responsible for KIT- and Flt-3L-independent kinase activation in other malignancies, including acute myeloid leukemia, mast cell disorders, and seminomas. KIT and PDGFRA mutations and overexpression are usually mutually exclusive in GIST. Thirty-five percent of KIT wild-type GISTs have PDGFRA mutations. Mutations in both KIT and PDGFRA lead to dysregulation of downstream intracellular signaling processes involving protein kinases and transcription factors such as AKT, MAPK, and STATs (STAT1 and STAT3), which play a critical role in the development and progression of cancer.

Morphologically, GIST are characterized as spindle cell type (70%), epithelioid (20%) or mixed (10%). GIST are most common in the stomach or duodenum, followed by the remainder of the small intestine, rectum, and esophagus. GIST may also be found in the colon, mesentery, or retroperitoneum, but this is much less common. About 10% to 20% of patients present with metastatic disease at the time of diagnosis, predominantly with involvement of the liver, omentum, or peritoneum.

CLINICAL PRESENTATION

Small GIST may be asymptomatic and are usually found incidentally during imaging or endoscopy studies. Larger tumors may cause symptoms related to their location.

Pain

Bloating

Early satiety

Bleeding

PROGNOSTIC FACTORS

Factors associated with an increased risk for recurrence of GIST include tumor size, mitotic index, tumor location, and presence of rupture of the tumor (Table 8.1). Based on these tumor characteristics, patients can be stratified into very low, low, intermediate, or high risk of recurrence. Tumors less than 2 cm have very low risk while tumors greater than 10 cm are associated with high risk. A mitotic index of ≤5 per 50 high power fields is associated with a very low or low risk for recurrence. A mitotic index of greater than 10 leads to a high risk. Tumor rupture is prognostic for a high risk of recurrence regardless of tumor size or mitotic index. Gastric GISTs are associated with a better outcome than GISTs in other locations.

TABLE 8.1 Modified NIH Risk Stratification for Recurrence of GIST

Risk	Size (cm)	Mitotic Index (per 50 HPFs)	Primary Tumor Site
Very low	<2	≤5	Any
Low	2.1 to 5	≤5	Any
Intermediate	2.1 to 5	>5	Gastric
	<5	6 to 10	Any
	5.1 to 10	≤5	Gastric
High	Any	Any	Tumor rupture
	>10	Any	Any
	Any	>10	Any
	>5	>5	Any
	2.1 to 5	>5	Any
	2.1 to 5	>5	Nongastric
	5.1 to 10	≤5	Nongastric

HPFs, high-power fields. Adapted from Joensuu H. Hum Pathol. 2008;39:1411.

DIAGNOSIS

Computerized tomography (CT) scans of the abdomen and pelvis with contrast or MRI are recommended for initial staging to determine the resectability of the tumor and to evaluate for metastatic disease. Endoscopy with ultrasound may be used to further characterize submucosal GI lesions and a fine needle aspiration during this procedure may be used to collect tissue for cytology and immunohistochemistry to establish a diagnosis. These biopsies are not required for patients who have a resectable tumor with a high degree of suspicion for GIST. A biopsy should be obtained in patients with clearly unresectable tumors or with tumors that may become resectable if treated with preoperative imatinib. Positron emission tomography (PET) scans are not routinely used for the diagnosis or monitoring of patients with GIST.

TREATMENT

Upfront resection is generally the standard for resectable disease in patients with no contraindications to surgery. Preoperative imatinib may impact the assessment of the risk of recurrence and should be reserved for patients in whom a decrease in the size of the tumor will minimize the morbidity of the surgery. Following resection of the tumor, patients with an intermediate or high risk of recurrence (Table 8.1) should start adjuvant therapy with imatinib for at least 3 years. Patients who received neoadjuvant imatinib followed by a complete resection and patients who have residual disease after surgery should receive postoperative imatinib. During treatment, patients should be seen in clinic with a CT of the abdomen and pelvis every 3 to 6 months for 3 to 5 years, with surveillance annually afterward. Approximately 60% of patients with resected GIST will be cured with surgery alone. The median time to recurrence after resection of a primary high-risk GIST is about 2 years; however, metastatic disease can develop several years after initial resection of the primary tumor necessitating long-term clinical follow-up.

Patients with unresectable or metastatic disease at the time of their diagnosis should start treatment with imatinib and have repeat imaging with CT scans after 3 months to assess treatment response. Patients with initially unresectable disease who have a response to imatinib should be assessed again for possible resection although downstaging with neoadjuvant therapy generally requires several months of treatment. Patients who continue to have unresectable tumors or who have metastatic disease with stable disease or a response to therapy should remain on imatinib indefinitely.

Patients with recurrent GIST should be treated with imatinib, if not given previously. Treatment options for patients with recurrence who have received prior imatinib or progression of their GIST while receiving imatinib include resection, embolization, radiofrequency ablation, or palliative radiation, escalation of the dose of imatinib, or alternative agents such as sunitinib and regorafenib. Mutational testing of the tumor may help with therapeutic decisions. Tumors with a KIT exon 9 mutation may be more likely to benefit from an increase in the dose of imatinib from 400 mg daily to 800 mg daily. GIST tumors with a PDGFRA D842V mutation or without a mutation in KIT or PDGFRA have a decreased likelihood of response to imatinib.

Patients with GIST tumors in the stomach measuring less than 2 cm without high risk EUS features, such as irregular borders, cystic spaces, ulceration, foci of echogenicity, and heterogeneity, may be managed by surveillance with endoscopy and may not require surgery.

ADJUVANT THERAPY

Imatinib is approved as adjuvant therapy for patients with GIST based on the results of the American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Z9001 study. In this phase III trial, 713 patients were randomized to 1 year of imatinib 400 mg daily or placebo following complete gross resection of a primary GIST expressing KIT measuring at least 3 cm. Upon recurrence, patients were allowed to crossover to from placebo to imatinib or increase the dose of imatinib to 800 mg daily. Recurrence-free survival (RFS) at 1 year, the primary endpoint of the trial, was 98% in the imatinib arm versus 83% in the placebo arm (P < 0.0001). Overall survival (OS) was not statistically significant between the two arms, likely due to the short-term follow-up and the crossover from placebo to imatinib. A subsequent study in patients with a high risk for recurrence showed an improvement in both 5-year RFS (65.6% vs. 47.9% (P<0001)) for patients receiving 3 years versus 1 year of imatinib, respectively. There was also an improvement in OS (92.0% vs. 81.7% in the 3-year and 1-year arms, respectively (P = 0.02)).

NEOADJUVANT THERAPY

A prospective phase II trial, RTOG 0132/ACRIN 6665, evaluated the safety and efficacy of neoadjuvant treatment with imatinib for 8 to 12 weeks before surgery with continuation of imatinib for at least 2 years after surgery or disease progression. Patients had a resectable KIT positive GIST measuring at least 5 cm. In patients with a primary GIST, there was a partial response in 7% of patients and stable disease in 83%. There was 5% partial response and stable disease in 91% of patients with resectable metastatic disease. With a median follow-up of 5 years, the PFS rate for patients with a primary tumor was 57% and OS rate was 77%. Complications of surgery and toxicity from the imatinib were minimal.

DRUGS USED FOR TREATING PATIENTS WITH GIST

Imatinib

Imatinib is a tyrosine kinase inhibitor of c-KIT and PDGFRA receptors. Imatinib is approved for patients with unresectable or metastatic KIT (CD117) positive GIST or for adjuvant treatment after resection of KIT positive GIST. Two large randomized phase III trials confirmed the efficacy of imatinib in patients with advanced GIST. In the S0033 trial, patients were randomized to receive either 400 mg of imatinib once daily (with crossover to 800 mg per day with disease progression) or 400 mg twice daily. The median OS was 55 months and 51 months for patients receiving 400 mg and 800 mg imatinib daily, respectively. There were no significant differences in response rates, PFS, or OS between the two groups. In a subgroup analysis of a retrospective analysis, patients with KIT exon 9 mutations receiving 800 mg imatinib daily had an improvement in PFS, but not in OS. Approximately 80% of patients eventually develop secondary mutations in KIT exons resulting in progressive disease. Patients should start therapy at 400 mg daily, and increase to 800 mg daily for patients with progression of disease or have the presence of an exon 9 KIT mutation. Treatment with imatinib is generally well tolerated with nausea, diarrhea, periorbital edema, muscle cramps, fatigue, headache, and dermatitis as the most common toxicities.

Sunitinib

Sunitinib is an oral inhibitor of several tyrosine kinase receptors approved for the patients with GIST after disease progression on or intolerance to imatinib. In a double-blind placebo-controlled, multicenter, randomized phase III trial, patients with GIST with disease progression on or intolerance to imatinib were randomized to receive sunitinib 50 mg daily for 4 weeks, with 2 weeks off (n = 207) or placebo (n = 105). Objective response rates in the sunitinib and placebo arms were 8% and 0%, respectively, and the median time to progression was significantly longer in the sunitinib arm (6.3 vs. 1.5 months).

Regorafenib

Regorafenib, an inhibitor of multiple tyrosine kinases including KIT and PDGFRA is approved for patients who have progressed after imatinib and sunitinib. In a randomized phase III trial, the median PFS was 4.8 months for patients receiving regorafenib and 0.9 months for patients receiving placebo (HR 0.27; P < 0.0001).